A randomized trial on the effect of transcutaneous electrical nerve stimulator on glycemic control in patients with type 2 diabetes

Transcutaneous electrical nerve stimulator (TENS) has been demonstrated to be beneficial in glycemic control in animal models, but its application in humans has not been well studied. We randomly assigned 160 patients with type 2 diabetes on oral antidiabetic drugs 1:1 to the TENS study device (n = 81) and placebo (n = 79). 147 (92%) randomized participants (mean [SD] age 59 [10] years, 92 men [58%], mean [SD] baseline HbA1c level 8.1% [0.6%]) completed the trial. At week 20, HbA1c decreased from 8.1% to 7.9% in the TENS group (− 0.2% [95% CI − 0.4% to − 0.1%]) and from 8.1% to 7.8% in the placebo group (− 0.3% [95% CI − 0.5% to − 0.2%]) (P = 0.821). Glycemic variability, measured as mean amplitude of glycemic excursion (MAGE) at week 20 were significantly different in the TENS group vs. the placebo group (66 mg/dL [95% CI 58, 73] vs. 79 mg/dL [95% CI 72, 87]) (P = 0.009). Our study provides the clinical evidence for the first time in humans that TENS does not demonstrate a statistically significant HbA1c reduction. However, it is a safe complementary therapy to improve MAGE in patients with type 2 diabetes.


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injectables within 3 months. 4. Subject has had any of the following new diagnoses within 1 year of screening: myocardial infarction, coronary artery bypass surgery, coronary artery stenting, transient ischemic attack, cerebrovascular accident, angina, congestive heart failure (NYHA III-IV), ventricular rhythm disturbances or thromboembolic disease. 5. Subjects with prior pancreatitis.
6. Subjects with insulin therapy (except for short term uses no longer than 7 days) or injectables within 3 months.
7. Woman with a positive pregnancy test, planning to become pregnant during screening, active treatment, or the follow up period, breastfeeding, or judged to be using inadequate contraceptive methods.
8. Subjects who underwent previous intra-abdominal, GI tract surgery or a major abdominal trauma within 6 months prior to screening visit. 9. Subjects with other implanted electrical stimulation devices.
10. Subject has any unresolved adverse skin condition in device placement.
11. ALT/AST greater than 3 x upper limit of the institution's normal range (ULN) and/or total bilirubin ≥ 2.0 x ULN, active liver disease (other than nonalcoholic hepatic steatosis), including chronic active hepatitis B or C, hepatic cirrhosis, primary biliary cirrhosis, or active symptomatic gallbladder disease.
13. Subjects with blood dyscrasias or any disorders causing hemolysis or unstable red blood cells or any other clinically significant hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia, coagulopathy).
14. Subjects with acute metabolic complications (such as ketoacidosis, lactic acidosis or hyperosmolar), proliferative diabetic retinopathy or macular edema within 6 months before screening.
15. Subjects with a history of malignancy ≤5 years prior to screening, except for adequately treated basal or squamous cell skin cancer or in situ cervical cancer.
16. Subjects with a history of alcohol or drug abuse within 1 year prior to screening.
17. Subjects who received another investigational agent within 30 days prior to screening.
18. Subjects who are unlikely to be available for follow-up as specified in the protocol.
19. Subjects with a past or present psychiatric condition that may impair his or her ability to comply with the study procedures. 20. Subjects with conditions that, in the judgment of the investigator, precludes successful participation to the study.

Sample size determination
The primary efficacy endpoint is to compare the change of HbA1c following a 20-week treatment of DW1330 versus placebo. According to prior published clinical reference and unpublished data on DW1330, we assumed that the mean HbA1c reduction is 5.5 mmol/mol.
The evaluable subject number should be at least 64 subjects for each group under these conditions: the one-sided significance level is 0.025, the power is 80%, the difference between control and experimental group is 5.5 mmol/mol, and the standard deviation of both treatment groups is 10.9 mmol/mol. Considering a 20% drop-out rate, a sample size of 80 subjects should be enrolled in each group, and a total of 160 subjects will be recruited into this study.

Study visits
At randomization visit study device was dispensed at the study site of six hospitals: National Taiwan University Hospital, National Cheng Kung University Hospital, Shuang Ho Hospital, Chi Mei Medical Center, Far Eastern Memorial Hospital, and Ditmanson Chia-Yi Christian Hospital. During the treatment period visits, all treatment emergent adverse events (TEAEs) as well as vital signs, changes to concomitant medications, efficacy evaluations were recorded, and blood and urine samples were collected. Investigators, site staff, subjects, and the study team were blinded to the device assigned. The end-of-treatment visit and the last estimation of glycemia occurred at week 20 (visit 8) for all subjects. In addition, a 2-week follow-up occurred to collect safety data after the device was returned. The final visit was at week 22 (visit 9). Subjects were encouraged to complete all planned visits regardless of their adherence to study device administration. A permuted block randomization method with 1: 1 ratio was employed to randomize subjects into one of the two arms as follows, (1) DW1330 treatment group or (2) Placebo group. The study duration was three years; and dates defining the periods of recruitment and follow-up were 19 July 2017 (the recruitment of the first case) and 15 July 2020 (the follow-up of the last case).

Randomization
A randomization code list and the random allocation sequence were generated by Bestat Pharmaservices Corp. and provided to Taiwan Resonant Waves Research Corp. to pack and label the study devices. Randomization data were not accessible by anyone else involved in the study. The corresponding study groups of individual subjects were recorded in a sealed envelope and kept strictly confidential until the time of data lock.

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The study device, "Dragon Waves Resonant Home Care" Electronic Nerve Stimulator (DW1330), indicated to relieve pain, reduce the sensitivity of peripheral nerve system, and stimulate blood circulation, has been approved for marketing in Taiwan. DW1330 uses fullfrequency wave resonant technology while the principle is like other electrical stimulation devices, such as transcutaneous electrical nerve stimulator (TENS), low frequency therapeutic device, or middle frequency stimulator. Subjects received their study device and applicable training and were instructed to use the device 1 hour after dinner by attaching the patches to the left and right side, around 5-10 cm from the navel as shown in eAppendix. The frequency of device use was one hour per day, 5 days/week.

Definition of study populations
These analysis populations were defined as following: ITT population is the randomized subjects who met all the inclusion and none of the exclusion criteria, used at least one time of the study device and had at least one post-randomization measurement. PP population is the subset of the ITT population who completed 20 weeks of treatment without major protocol violation. The definitions of major violations include: 1. device compliance less than 70%; 2. violation of eligibility criteria; 3. use of prohibited medications. Safety population is all randomized subjects who used at least one time of the study device.

Data management
Data management and statistical analysis was conducted by Bestat Pharmaservices Corp.
The data manager generated queries using data clarification forms to the site personnel when there were any potential errors, omissions, or unlikely values in the data. After confirming all the discrepancies and resolving all queries, the database was locked by the data manager in line with the standard operating procedures. The last observation carried forward (LOCF) method would be adopted to establish this missing efficacy value. *Statistically significant. The last observation carried forward (LOCF) method would be adopted to establish this missing efficacy value. *Statistically significant. The last observation carried forward (LOCF) method would be adopted to establish this missing efficacy value. *Statistically significant. Abbreviations: SD, standard deviation; CI, confidence interval. Paired t-test was conducted.

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The last observation carried forward (LOCF) method would be adopted to establish this missing efficacy value. *Statistically significant.   Abbreviations: CRP, C-reactive protein; TNF-α, tumor necrosis factor-α; FGF-21, fibroblast growth factor-21. Two-sample t-test was conducted for continuous variable. Data are presented as means (SD).

Differences within the group of CRP mean change from baseline in ITT population
week  inconvenience or concern to the subject and may interfere with daily activities, but was usually by simple therapeutic remedy; Severe: Interrupted a subject's daily activity and typically required intervening treatment. daily activity; Moderate: Low level of inconvenience or concern to the subject and may interfere with daily activities, but was usually by simple therapeutic remedy; Severe:

Summary of AE related to study device by System Organ Class and Preferred
Interrupted a subject's daily activity and typically required intervening treatment.  The study device, "Dragon Waves Resonant Home Care" Electronic Nerve Stimulator (DW1330), indicated to relieve pain, reduce the sensitivity of peripheral nerve system, and stimulate blood circulation, has been approved for marketing in Taiwan. The impulses are sent through wires to patches which are placed at appropriate body sites. DW1330 uses fullfrequency wave resonant technology while the principle is similar to other electrical stimulation devices, such as transcutaneous electrical nerve stimulation, low frequency therapeutic device, or middle frequency stimulator, but it is applied with different frequency between 1 and 100

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Hertz (HZ). During the stimulation period, DW1330 will deliver predefined different mixed frequency. DW1330 is a small portable, battery-operated device along with wires and 2 patches. The blueprint of DW1330 and the design of mixed frequency are shown in Figure 1 and Figure 2. The model of electronic stimulation is shown in Figure 3.

Animal Study
In pre-clinical setting, DW1330 has been proven to significantly improve glucose regulation in animal model, as indicated by fasting plasma glucose (FPG) and HbA1c (refer to Figure 4 and Figure 5). The study is reported in accordance with ARRIVE guidelines Blood Glucose Control-60 minutes

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(https://arriveguidelines.org). After a 6-week treatment period, FPG did not differ between the healthy mice without resonant wave treatment, healthy mice with resonant wave treatment, and diabetic mice receiving resonant wave treatment, but it achieved statistically significant difference between the diabetic mice with and without resonant wave treatment. As for HbA1c, the value was much lower in diabetic mice treated with resonant wave as compared with those without resonant wave treatment (5.4% in diabetic mice with resonant wave treatment versus 7.6% in diabetic mice without resonant wave treatment). The effects of resonant wave treatments on vital organs were evaluated after the mice were sacrificed by carbon dioxide (CO2) inhalation, and results showed that resonant wave intervention reversed the pathological changes on liver, kidney, pancreas, epididymal adipose tissues, and lung in mice with diabetes mellitus induced by streptozotocin. The results indicated that DW1330 could reduce FPG level and HbA1c and was safe in animal model.

Human Study
In an unpublished study conducted in Taiwan, subjects were randomized to either receive DW1330 or placebo for 12 weeks and then crossed over to the alternate arm for 12 weeks.
Subjects were instructed to use the device (with effective or ineffective frequency) for 60 minutes daily for 5 days per week during the study period. The results showed that DW1330 significantly improved glycemic control in T2DM patients, as indicated by HbA1c. The HbA1c level decreased by approximately 0.5% in patients with higher body mass index (≥26 kg/m 2 ) after a 12-week treatment with DW1330.
Subjects received their study device and applicable training and were instructed to use the device 1 hour after dinner by attaching the patches to the left and right side, around 5-10 cm from the navel as shown in Figure 6. The frequency of device use was one hour per day, 5 days/week.